Stroke (focal cerebral ischemia) is a leading cause of death and disability in aging Veterans. Furthermore, many aged Veterans also suffer from neurodegenerative disorders. The mechanisms that contribute to secondary brain damage and neurological dysfunction after stroke are not completely understood. Preliminary studies of this proposal show induction of a-Synuclein expression in the brains of rodents subjected to focal ischemia. As a-Synuclein is thought to be a major contributor of neuronal death in Parkinson Disease and other chronic neurodegenerative diseases, the present proposal will test the hypothesis a-Synuclein is a contributor of post-stroke brain damage. This hypothesis will be tested by the following Specific Aims: Aim 1 is to evaluate the functional significance of a-Synuclein in promoting secondary brain damage and neurological dysfunction following experimental stroke using a-Synuclein siRNA-mediated knockdown and a-Synuclein knockout mice as alternate approaches. Aim 2 is to evaluate if down-regulation of microRNA miR-7a is responsible for a-Synuclein protein induction in the post-ischemic brain. We will test if restoring miR-7a levels with a miR mimic curtails a- synuclein mediated post-ischemic secondary brain damage and neurological dysfunction. Aim 3 is to identify if a-Synuclein induced after stroke mediates secondary brain damage by modulating inflammation, oxidative stress, apoptosis, mitochondrial fission, and autophagy. We will test if a- Synuclein knockdown curtails these post-ischemic pathophysiological mechanisms and thus decreases post-ischemic brain damage. Aim 4 is to test the role of post-translational modifications of a-Synuclein in ischemic brain damage. We will specifically study ser-129 phosphorylation which is thought to promote a-Synuclein oligomerization and toxicity and lysine ubiquitination which is thought to be important for a-Synuclein degradation by lysosomes. Aim 5 is to study the long-term implications of a-Synuclein induction after stroke. This is important as a- Synuclein accumulation and toxicity occur over decades in chronic neurodegenerative conditions; whereas a-Synuclein increases rapidly within hours after stroke. Overall, the present project will serve as a bridge to understan the role of a-Synuclein and to design novel therapies based on a-Synuclein and miRNA-7a to minimize the post-stroke brain damage in Veterans. Relevance of the proposed work to the VA patient care mission: Every year, >7,000 Veterans suffer new strokes and there are >80,000 surviving Veterans with stroke-induced neurological dysfunction. The negative impact of this devastating disease on Veterans increases enormously in the near future unless the molecular mechanisms of post-stroke brain damage are deciphered and therapies are developed based on the new targets. a-Synuclein is an attractive target to curtail post-stroke brain damage as many resources are already available from the ongoing research on Parkinson Disease. Successful completion of the proposed studies to evaluate the significance of a-Synuclein after stroke helps the recovery of surviving stroke sufferers among Veterans.